Skip to main content
SpringerLink
Log in

Evodiamine inhibits growth of vemurafenib drug-resistant melanoma via suppressing IRS4/PI3K/AKT signaling pathway

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

Evodiamine, a novel alkaloid, was isolated from the fruit of tetradium. It exerts a diversity of pharmacological effects and has been used to treat gastropathy, hypertension, and eczema. Several studies reported that evodiamine has various biological effects, including anti-nociceptive, anti-bacterial, anti-obesity, and anti-cancer activities. However, there is no research regarding its effects on drug-resistant cancer. This study aimed to investigate the effect of evodiamine on human vemurafenib-resistant melanoma cells (A375/R cells) proliferation ability and its mechanism. Cell activity was assessed using the cell counting kit-8 (CCK-8) method. Flow cytometry assay was used to assess cell apoptosis and cell cycle. A xenograft model was used to analyze the inhibitory effects of evodiamine on tumor growth. Bioinformatics analyses, network pharmacology, and molecular docking were used to explore the potential mechanism of evodiamine in vemurafenib-resistant melanoma. RT-qPCR and Western blotting were performed to reveal the molecular mechanism. The alkaloid extract of the fruit of tetradium, evodiamine showed the strongest tumor inhibitory effect on vemurafenib-resistant melanoma cells compared to treatment with vemurafenib alone. Evodiamine inhibited vemurafenib-resistant melanoma cell growth, proliferation, and induced apoptosis, conforming to a dose–effect relationship and time–effect relationship. Results from network pharmacology and molecular docking suggested that evodiamine might interact with IRS4 to suppress growth of human vemurafenib-resistant melanoma cells. Interestingly, evodiamine suppressed IRS4 expression and then inhibited PI3K/AKT signaling pathway, and thus had the therapeutic action on vemurafenib-resistant melanoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Shi H, Hong A, Kong X, Koya RC, Song C, Moriceau G, Hugo W, Yu CC, Ng C, Chodon T, Scolyer RA, Kefford RF, Ribas A, Long GV, Roger Lo S (2014) A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov 4:69–79

    Article  CAS  PubMed  Google Scholar 

  2. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AMM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, BRIM-3 Study Group (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jiang CC, Lai F, Thorne RF, Yang F, Liu H, Hersey P, Zhang XD (2010) MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res 17:721–730

    Article  PubMed  Google Scholar 

  7. Cheung M, Sharma A, Madhunapantula SV, Robertson GP (2008) Akt3 and mutant V600EB-Raf cooperate to promote early melanoma development. Can Res 68:3429–3439

    Article  CAS  Google Scholar 

  8. Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D (2009) Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 69:565–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. She QB, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T, Solit DB, Rosen N (2010) 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 18:39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gopal YNV, Deng W, Woodman SE, Komurov K, Ram P, Smith PD, Davies MA (2010) Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Can Res 70:8736–8747

    Article  CAS  Google Scholar 

  11. Javier Delgado-Lista P, Perez-Martinez JS, Antonio Garcia-Rios AI, Perez-Caballero JA, Lovegrove CA, Drevon CD, Blaak EE, Dembinska-Kieć A, Risérus U, Herruzo-Gomez E, Camargo A, Ordovas JM, Roche H, Lopez-Miranda J (2014) Top single nucleotide polymorphisms affecting carbohydrate metabolism in metabolic syndrome: from the LIPGENE study. J Clin Endocrinol Metab 99:384–389

    Article  Google Scholar 

  12. Wang T, Qi D, Hu X, Li N, Zhang J (2021) A novel evodiamine amino derivative as a PI3K/AKT signaling pathway modulator that induces apoptosis in small cell lung cancer cells. Eur J Pharmacol 906:174215

    Article  CAS  PubMed  Google Scholar 

  13. Tianyu Meng SFu, He D, Guiqiu Hu, Gao X, Zhang Y, Huang B, Jian Du, Zhou A, Yingchun Su, Liu D (2021) Evodiamine inhibits lipopolysaccharide (LPS)-induced inflammation in BV-2 cells via regulating AKT/Nrf2-HO-1/NF-κB signaling axis. Cell Mol Neurobiol 41:115–127

    Article  PubMed  Google Scholar 

  14. Hui Yu, Jin H, Gong W, Wang Z, Liang H (2013) Pharmacological actions of multi-target-directed evodiamine. Molecules 18:1826–1843

    Article  Google Scholar 

  15. Fei Liu Z-B, He H-Y, Liu J-S, Yang W-D (2016) Inhibition of five natural products from Chinese herbs on the growth of Chattonella marina. Environ Sci Pollut Res Int 23:17793–17800

    Article  PubMed  Google Scholar 

  16. Vijay Mohan RA, Singh RP (2016) A novel alkaloid, evodiamine causes nuclear localization of cytochrome-c and induces apoptosis independent of p53 in human lung cancer cells. Biochem Biophys Res Commun 477(4):1065–1071

    Article  PubMed  Google Scholar 

  17. Ze-Bo Jiang J-M, Huang Y-J, Zhang Y-Z, Chang C, Lai H-L, Wang W, Yao X-J, Fan X-X, Qi-Biao Wu, Xie C, Wang M-F, Leung E-H (2020) Evodiamine suppresses non-small cell lung cancer by elevating CD8+ T cells and downregulating the MUC1-C/PD-L1 axis. J Exp Clin Cancer Res 39:249

    Article  PubMed  PubMed Central  Google Scholar 

  18. Le Seung Yeob Hyun HT, Min H-Y, Pei H, Lim Y, Song I, Nguyen YTK, Hong S, Han BW, Lee H-Y (2021) Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70. Theranostics 11(6):2932–2952

    Article  PubMed  PubMed Central  Google Scholar 

  19. Panda M, Biswal BK (2022) Evodiamine inhibits stemness and metastasis by altering the SOX9-β-catenin axis in non-small-cell lung cancer. J Cell Biochem 123:1454–1466

    Article  CAS  PubMed  Google Scholar 

  20. Junlin Jiang CHu (2009) Evodiamine: a novel anti-cancer alkaloid from Evodia rutaecarpa. Molecules 14:1852–1859

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chaodan Luo J, Ai ER, Li J, Feng C, Li X, Luo X (2021) Research progress on evodiamine, a bioactive alkaloid of Evodiae fructus: focus on its anti-cancer activity and bioavailability. Exp Ther Med 22:1327

    Article  PubMed  PubMed Central  Google Scholar 

  22. Cho-Hwa Liao S-L, Pan J-H, Chang Y-L, Pai H-C, Lin C-H, Teng C-M (2005) Antitumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus, in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo. Carcinogenesis 26:968–975

    Article  PubMed  Google Scholar 

  23. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13(10):714–726

    Article  CAS  PubMed  Google Scholar 

  24. Triggle CR, Mohammed I, Bshesh K, Marei I, Ye K, Ding H, MacDonald R, Hollenberg MD, Hill MA (2022) Metformin: is it a drug for all reasons and diseases? Metabolism 133:155223

    Article  CAS  PubMed  Google Scholar 

  25. Aljada A, Saleh AM, Suwaidan AIS (2014) Modulation of insulin/IGFs pathways by sirtuin-7 inhibition in drug-induced chemoreistance. Diagn Pathol 9:94

    Article  PubMed  PubMed Central  Google Scholar 

  26. Klijn C, Koudijs MJ, Kool J, ten Hoeve J, Boer M, de Moes J, Akhtar W, van Miltenburg M, Vendel-Zwaagstra A, Reinders MJT, Adams DJ, van Lohuizen M, Hilkens J, Wessels LFA, Jonkers J (2013) Analysis of tumor heterogeneity and cancer gene networks using deep sequencing of MMTV-induced mouse mammary tumors. PLoS One 8(5):e62113

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang X, Zhu X, Bi X, Huang J, Zhou L (2022) The insulin receptor: an important target for the development of novel medicines and pesticides. Int J Mol Sci 23:7793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ikink GJ, Boer M, Bakker ERM, Hilkens J (2016) IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation. Nat Commun 7:13567

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gong Y, Ma Y, Sinyuk M, Loganathan S, Thompson RC, Sarkaria JN, Chen W, Lathia JD, Mobley BC, Clark SW, Wang J (2016) Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation. Neuro Oncol 18(1):48–57

    Article  CAS  PubMed  Google Scholar 

  30. Möhlig M, I F, Ristow M (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:2419–2421

    Article  PubMed  Google Scholar 

  31. Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sullivan RJ, LoRusso PM, Flaherty KT (2013) The intersection of immune-directed and molecularly targeted therapy in advanced melanoma: where we have been, are, and will be. Clin Cancer Res 19(19):5283–5291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mountzios G, Terpos E, Dimopoulos M-A (2008) Aurora kinases as targets for cancer therapy. Cancer Treat Rev 34(2):175–182

    Article  CAS  PubMed  Google Scholar 

  34. Napolitano S, Matrone N, Muddassir AL, Martini G, Sorokin A, Falco VD, Giunta EF, Ciardiello D, Martinelli E, Belli V (2019) Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression. J Exp Clin Cancer Res 38:1–18

    Article  Google Scholar 

  35. Li X, Wu S, Dong G, Chen S, Ma Z, Liu D, Sheng C (2020) Natural product Evodiamine with borate trigger unit: discovery of potent antitumor agents against colon cancer. ACS Med Chem Lett 11(4):439–444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chan BT-Y, Lee AV (2008) Insulin receptor substrates (IRSs) and breast tumorigenesis. J Mammary Gland Biol Neoplasia 13(4):415–422

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kang D-H, Kim SH, Jun JW, Lee Y-W, Shin HB, Ahn JY, Hong DS, Lee YK, Jeon BR (2012) Simultaneous translocation of both TCR Loci (14q11) with rare partner loci (Xq22 and 12p13) in a case of T-lymphoblastic leukemia. Ann Lab Med 32(3):220–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cantarini MC, de la Monte SM, Pang M, Tong M, D’Errico A, Trevisani F, Wands JR (2006) Aspartyl-asparagyl β hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatology 44(2):446–457

    Article  CAS  PubMed  Google Scholar 

  39. Garg A, Misra A (2004) Lipodystrophies: rare disorders causing metabolic syndrome. Endocrinol Metab Clin North Am 33:305–331

    Article  CAS  PubMed  Google Scholar 

  40. Zheng Z, Bian Y, Zhang Y, Ren G, Li G (2020) Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell Cycle 19:1089–1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. An Y, Wang B, Wang X, Dong G, Jia J, Yang Q (2020) SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop. Cell Death Dis 11:115

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dilmac S, Kuscu N, Caner A, Yildirim S, Yoldas B, Farooqi AA, Tanriover G (2022) SIRT1/FOXO signaling pathway in breast cancer progression and metastasis. Int J Mol Sci 23:10227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We appreciate the great assistance of Lab of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University.

Funding

This work was supported by the Technology Research Program of Chongqing Municipal Education Commission (No. KJZD-K201802701, to Dilong Chen). Chongqing Education Commission "Natural Medicine Anti-tumor" innovative research (No. CXQT20030, to Dilong Chen). Chongqing Talent Program, (No. cstc2022ycjh-bgzxm0226, to Dilong Chen), Selection and Development of indigenous medicinal materials in the Three Gorges Reservoir Area. And the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-M202202701, to Dilong Chen).

Author information

Authors and Affiliations

  1. Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China

    Xingxian Guo

  2. Department of Clinical Laboratory, Zigong First People’s Hospital, Zigong, China

    Shiying Huang

  3. Lab of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400010, China

    Lisha Li & Jing Li

  4. Department of Pharmacy, Women and Children’s Hospital of Chongqing Medical University, Department of Pharmacy, Chongqing Health Center for Women and Children), Chongqing, China

    Hong Wang

  5. Chongqing Engineering Research Center for Clinical Big-Data and Drug Evaluation Medical Data Science Academy, Chongqing Medical University, Chongqing, China

    Yonghong Zhang

  6. Neuroscience Research Center, College of Basic Medicine, Chongqing Medical University, Chongqing, China

    Jianhua Ran

  7. Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Faculty of Basic Medical Sciences, Chongqing Three Gorges Medical College, Wanzhou, 404100, China

    Dilong Chen & Xiaopeng Li

  8. NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing Institute for Food and Drug Control, Chongqing, China

    Dilong Chen

Authors
  1. Xingxian Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiying Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yonghong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lisha Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jianhua Ran
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dilong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaopeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XXG: designed research, performed research, analyzed data and wrote the paper. SYH, YHZ, and HW, designed and performed research. LSL, JHR, and DLC: provided technical support. SYH, HW, YHZ, XPL, and JL: corrected experiments and the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiaopeng Li or Jing Li.

Ethics declarations

Conflict of interest

XXG, SYH, YHZ, HW, LSL, JHR, DLC, XPL, and JL declare no conflict of interest.

Ethical approval

All animal experiments were got permission from the Animal Experimental Center of Chongqing Medical University and performed according to the U.K. Animals (Scientific Procedures) Act, 1986. The approval number of animal ethics is IACUC-CQMU-2023-0351.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, X., Huang, S., Zhang, Y. et al. Evodiamine inhibits growth of vemurafenib drug-resistant melanoma via suppressing IRS4/PI3K/AKT signaling pathway. J Nat Med 78, 342–354 (2024). https://doi.org/10.1007/s11418-023-01769-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-023-01769-9

Keyword

Search

Navigation